Objective: The objective of this proposal is to clarify the molecular mechanisms that regulate the pro- apoptotic effects of NRAGE in neural development, and to utilize this information in the future to design modulators of NRAGE function as indirect regulators of caspase activity and cell viability. Hypothesis: The basis of this proposal is that NRAGE functions as an indispensable component of the non-canonical Bone Morphogenetic Protein (BMP)-signaling pathway leading to p38MAPK and caspase activation. This may be the same that mediates the tumor death of human medulloblastoma patients undergoing retinoid therapy. New preliminary evidence demonstrates that the unique hexapeptide repeat of NRAGE is essential in mediating cortical progenitor apoptosis, the cells that underlie medulloblastoma formation. In addition this region binds the inhibitor of apoptosis protein Xiap. It stands to reason that discerning and altering this interaction will have great potential in regulating caspase activation and cell viability. In order to refine the role of NRAGE in neural progenitor apoptosis, we propose the following two Specific Aims: I. Elucidate the role of NRAGE in the non-canonical BMP signaling cascade resulting in BMP- induced p38MAPK activation and apoptosis of neural progenitors. A molecular dissection of the non- canonical BMP-signaling pathway will be undertaken to ascertain the role of NRAGE in neural progenitor apoptosis with emphasis on the formation of the TAK-TAB-NRAGE-XIAP complex needed to regulate non-canonical BMP signaling. II. Determine the role of canonical BMP signaling in regulating NRAGE protein expression. NRAGE expression and BMP-mediated apoptosis will be challenged in mice with abrogated canonical BMP signaling due to a conditional mutation in the Smad4 gene in neural progenitors. We suggest that the proposed studies will clarify the function of NRAGE, and thus will have broad significance to the neuroscience community. Also, the identification and manipulation of NRAGE: Xiap interactions may enhance the utility of NRAGE as a therapeutic target in manipulating caspase activity to combat a variety of human diseases, especially medulloblastoma. [unreadable] [unreadable]